Beta-ketophosphonates

ABSTRACT

A method for making β-ketophosphonates by reacting a trialkyl phosphonocarboxylate (such as triethyl phosphonoacetate) with an acyl halide (such as acetyl chloride) in a reaction involving ester formation, followed by decarboxylation, followed by purification. The reaction is run in a single solvent, which is not removed from the reaction mixture until the purification stage. Suitable solvents for this purpose include halogenated aromatic hydrocarbons (such as mono-chlorobenzene).

[0001] This invention relates to beta-ketophosphonates and in particularto an improved method for the production of beta-ketophosphonates. Thepresent invention also relates to beta-ketophosphonates produced by wayof the aforesaid method.

[0002] Beta-ketophosphonates are known as valuable intermediates in thesynthesis of α, β-unsaturated carbonyl compounds by theHorner-Wadsworth-Emmons reaction and also for use in the liquid/liquidextraction of metals.

[0003] Typically, beta-ketophosphonates are produced by the reaction ofthe anion of a dialkyl methyl phosphonate with a carboxylic ester orhalide, at low temperatures (e.g. −70° C.). The present inventionrelates to a method in which beta-ketophosphonates are produced moreconveniently by the reaction of a trialkyl phosphonocarboxylate, via itsmagnesium “enolate”, with an acyl halide, at ambient temperatures (e.g.20° C.). This reaction takes place in three stages, namely intermediateester formation, decarboxylation and purification. Hitherto, the firststage of the reaction has been carried out using dichloromethane as asolvent for the phosphonocarboxylate. The solvent has to be removed atthe end of the first (ester formation) stage, only to be added again andsubsequently removed again at the beginning and end respectively of thethird (purification) stage. The need to add, remove, add and removedichloromethane has made this reaction uneconomic to work on anindustrial scale.

[0004] The applicants have unexpectedly found that replacement of thedichloromethane solvent by a halogenated aromatic hydrocarbon avoids theneed to strip out the solvent at the end of the first stage of thereaction, reduces hydrolysis of the decarboxylated product at the secondstage and improves the purity and yield of the beta-ketophosphonatesobtained at the end of the third stage.

[0005] Accordingly, the present invention provides a method for theproduction of a beta-ketophosphonate by the reaction of a trialkylphosphonocarboxylate with an acyl halide, said reaction proceeding byway of a first, intermediate ester formation, stage, a second,decarboxylation, stage and a third, purification, stage, in which saidreaction is carried out in a single solvent, said solvent not beingremoved until the third, purification stage of said reaction.

[0006] Preferably, the solvent used in accordance with the method of thepresent invention is a halogenated aromatic hydrocarbon. A particularlypreferred solvent is monochlorobenzene.

[0007] The use of monochlorobenzene (b.p. 132° C.) instead ofdichloromethane (b.p. 40° C.) makes the method inherently safer (thesolvent acts as a heat-sink for the reaction) as well as moreindustrially applicable. The need to add more solvent or to dry thecrude product of the second, decarboxylation, stage, is avoided. Thesolvent is removed (e.g. by vacuum-distillation) at the end of thereaction and aqueous work-up procedure.

[0008] The first, intermediate ester formation, stage convenientlyproceeds by way of a magnesium “enolate” of the starting trialkylphosphonocarboxylate. This first stage is typically carried out in thepresence of a base, with subsequent hydrolysis to produce intermediateester.

[0009] The trialkyl phosphonocarboxylate may suitably be triethylphosphonoacetate or trimethyl phosphonoacetate. It may conveniently beformed into the corresponding magnesium “enolate” by the action ofmagnesium chloride.

[0010] The base is preferably a tertiary amine such as triethylamine.

[0011] The acyl halide may be acetyl chloride or isobutyryl chloride.Other acyl halides include hydrocinnamoyl (3-phenylpropionyl) chloride,valeryl (pentanoyl) chloride and caproyl (hexanoyl) chloride.

[0012] Hydrolysis to form the intermediate ester may be achieved by theuse of a dilute mineral acid, for example hydrochloric acid.

[0013] The second, decarboxylation, stage may be achieved by theaddition of a small amount of water to the solution of the intermediateester in chlorobenzene, followed by heating of the mixture to 100-110°C. Excess water and alcohol, formed as a by-product of thedecarboxylation, is distilled from the reactor at this stage.

[0014] The product of the second, decarboxylation, stage is thenvacuum-stripped to remove the solvent, typically giving rise to ahigh-purity (more than 98% pure) and a high-yield (more than 95% yield)product.

[0015] The present invention further provides beta-ketophosphonatesprovided by the method hereinabove described.

[0016] A preferred embodiment of the present invention will be describedby way of the following Examples.

EXAMPLE 1 Preparation of Diethyl-2-oxopropyl phosphonate

[0017] A reaction vessel was charged with magnesium chloride (31.7 g)and chlorobenzene (550 g). Triethylphosphonoacetate (74.7 g) was thenadded to this over a period of 10 minutes at 20° C. Triethylamine (84.2g) was subsequently added to this mixture at 20° C. over 20 minutes,then stirred for 30 minutes at 20° C. Acetyl chloride (34.9 g) was thenadded to the reaction mixture at 20° C. over 45 minutes, and stirred fora further 30 minutes at 20° C. The reaction mixture was quenched with500 g 1M hydrochloric acid, which was added over 10 minutes and stirredfor 1 hour at 20° C. The organic and aqueous phases were allowed toseparate, and the organic layer containing the intermediate ester wasremoved from the reactor.

[0018] The organic layer was charged to a reactor configured fordistillation, together with 9 g of water. The mixture was heated for 4hours at 110° C. or until product purity, measured by ³¹P-NMR, wasgreater than 98%.

[0019] The organic mixture was subjected to an aqueous washingprocedure. The organic layer, containing the product, was separated andthe chlorobenzene solvent was removed by vacuum stripping to leave thetitle compound in high yield and purity.

EXAMPLE 2 Preparation of Diethyl-2-oxo-(3-methyl)butyl phosphonate

[0020] A reaction vessel was charged with magnesium chloride (19.0 g)and chlorobenzene (330 g). Triethylphosphonoacetate (44.8 g) was thenadded to this over a period of 10 minutes at 20° C. Triethylamine (50.5g) was subsequently added to this mixture at 20° C. over 20 minutes,then stirred for 30 minutes at 20° C. Isobutyryl chloride (24.5 g) wasthen added to the reaction mixture at 20° C. over 40 minutes, andstirred for a further 30 minutes at 20° C. The reaction mixture wasquenched with 300 g 1M hydrochloric acid, which was added over 10minutes and stirred for 1 hour at 20° C. The organic and aqueous phaseswere allowed to separate, and the organic layer containing theintermediate ester was removed from the reactor.

[0021] The organic layer was charged to a reactor configured fordistillation, together with 9 g of water. The mixture was heated for 4hours at 110° C. or until product purity, measured by ³¹P-NMR, wasgreater than 98%.

[0022] The organic mixture was subjected to an aqueous washingprocedure. The organic layer, containing the product, was separated andthe chlorobenzene solvent was removed by vacuum stripping to leave thetitle compound in high yield and purity.

EXAMPLE 3 Preparation of Dimethyl 2-oxo-(4-phenyl)butyl phosphonate

[0023] A reaction vessel was charged with magnesium chloride (19.0 g)and chlorobenzene (300 g). Trimethylphosphonoacetate (36.4 g) was thenadded to this over a period of 10 minutes at 20° C. Triethylamine (50.5g) was subsequently added to this mixture at 20° C. over 20 minutes,then stirred for 30 minutes at 20° C. Hydrocinnamoyl chloride (37.1 g)was then added to the reaction mixture at 20° C. over 40 minutes, andstirred for a further 30 minutes at 20° C. The reaction mixture wasquenched with 300 g 1M hydrochloric acid, which was added over 10minutes and stirred for 1 hour at 20° C. The organic and aqueous phaseswere allowed to separate, and the organic layer containing theintermediate ester was removed from the reactor.

[0024] The organic layer was charged to a reactor configured fordistillation, together with 6 g of water. The mixture was heated for 4hours at 110° C. until decarboxylation of the intermediate ester,determined by ³¹P-NMR, was complete, then allowed to cool.

[0025] The organic layer, containing the product, was separated and thechlorobenzene solvent was removed by vacuum stripping to leave the titlecompound in high yield and purity.

1-9. (Canceled).
 10. A method for the production of a beta-ketophosphonate by the reaction of a trialkyl phosphonocarboxylate with an acyl halide, said reaction proceeding by way of a first, intermediate ester formation, stage, a second, decarboxylation, stage and a third, purification, stage, in which said reaction is carried out in a single solvent, said solvent not being removed until the third, purification, stage of said reaction.
 11. A method according to claim 10, in which the solvent is a halogenated aromatic hydrocarbon.
 12. A method according to claim 11, in which the solvent is monochlorobenzene.
 13. A method according to claim 10, in which the first stage is carried out in the presence of a base.
 14. A method according to claim 13, in which the base is a tertiary amine.
 15. A method according to claim 14, in which the base is triethylamine.
 16. A method according to claim 10, in which the trialkyl phosphonocarboxylate is triethyl phosphonoacetate or trimethyl phosphonoacetate.
 17. A method according to claim 10, in which the acyl halide is acetyl chloride or isobutyryl chloride.
 18. A method according to claim 10, in which the acyl halide is hydrocinnamoyl chloride, valeryl chloride or caproyl chloride. 